# High-intensity focused ultrasound

(Redirected from HIFU)
High-intensity focused ultrasound
A schematic diagram showing the basic principle of HIFU for treatment of a soft tissue tumour in the liver. The focal region can be placed at depth within a tumour, where a series of adjacent ‘lesions’ known as a lesion array can be formed as shown.
Synonyms Magnetic resonance guided focused ultrasound surgery (MRgFUS), Focused Ultrasound Surgery (FUS)

High-intensity focused ultrasound (HIFU) is a non-invasive therapeutic technique that uses non-ionizing ultrasonic waves to heat tissue. HIFU can be used to increase the flow of blood or lymph, or to destroy tissue, such as tumors, through a number of mechanisms. The technology can be used to treat a range of disorders and as of 2015 is at various stages of development and commercialization. [1]

The technology is similar to ultrasonic imaging, although lower frequencies and continuous, rather than pulsed waves are used to achieve the necessary thermal doses. Acoustic lenses are used to achieve the necessary intensity at the target tissue without damaging the surrounding tissue. An analogy is using a magnifying glass to focus sunlight; only the focal point of the magnifying glass has high intensity. Although lenses have traditionally been used, phased arrays are increasingly common as they allow the focal position to be easily changed. HIFU may be combined with other imaging techniques such as medical ultrasound or MRI to enable guidance of the treatment and monitoring.

## Medical uses

There is no clear consensus on the boundaries between HIFU and other forms of therapeutic ultrasound. In academic literature, HIFU usually refers to the high levels of energy required to destroy tissue, although it is also sometimes used to describe lower intensity applications such as occupational therapy and physical therapy.

Either way, HIFU is used to non-invasively heat tissue deep in the body without making incisions. The main applications are the destruction of tissue, increasing perfusion and physical therapy. The use of ultrasound in the treatment of musculoskeletal conditions however is less common than it was.[2]

### Treatments With Approval (FDA or Otherwise)

Essential tremor, Parkinson's and other neurological disorders
A focused ultrasound system is approved in Israel, Europe, Korea and Russia to treat essential tremor,[3] neuropathic pain,[4] and Parkinsonian tremor.[5] This approach enables treatment of the brain without incisions and without radiation. In 2016, the US Food and Drug Administration (FDA) approved Insightec’s Exablate Neuro system to treat essential tremor.[6]
Treatment for symptomatic uterine fibroids became the first approved application of HIFU by the US Food and Drug Administration (FDA) in October 2004.[7] Studies have shown that HIFU is safe and effective, and that patients have sustained symptomatic relief is sustained for at least two years without the risk of complications involved in surgery or other more invasive approaches.[8] Up to 16-20% of patients will require additional treatment.[9]
Prostate cancer
HIFU is being studied in men with prostate cancer.[10][11]
Other cancers
HIFU has been successfully applied in treatment of cancer to destroy solid tumors of the bone, brain, breast, liver,[12] pancreas, rectum, kidney, testes, prostate.[13]
Palliative care

HIFU has been found to have palliative effects. CE approval has been given for palliative treatment of bone metastasis.[14] Experimentally, a palliative effect was found in cases of advanced pancreatic cancer.[15]

HIFU may also be used to produce heating for other purposes than cell destruction. For example, HIFU and other devices may be used to activate temperature-sensitive liposomes filled with cancer drug "cargo", to release the drug in high concentrations only at focused tumor sites and when triggered to do so by the hyperthermia device (See Hyperthermia therapy).

Cosmetic medicine

HIFU devices have been cleared to treat subcutaneous adipose tissue for the purposes of body contouring (known colloquially, and incorrectly since there is no suction involved, as "non-invasive liposuction"). These devices are available in the US,[16][17] Canada, the EU, Australia, and certain countries in Asia. HIFU is also cleared, with lower energy levels, for eyebrow lifts.[citation needed]

Other approved applications
An ultrasound-guided device received CE approval for thyroid nodule treatment in 2007, and in 2011 received CE approval for treatment of breast fibroadenoma.[citation needed]

Another device that is guided by optical cameras received CE approval for the treatment of glaucoma in 2011.[18]

## Method of use

HIFU beams are precisely focused on a small region of diseased tissue to locally deposit high levels of energy. The temperature of tissue at the focus will rise to between 65 and 85 °C, destroying the diseased tissue by coagulative necrosis. Higher temperatures are usually avoided to prevent boiling of liquids inside the tissue. Each sonication (individual ultrasound energy deposition) treats a precisely defined portion of the targeted tissue. The entire therapeutic target is treated by using multiple sonications to create a volume of treated tissue, according to a protocol developed by the physician. Anesthesia is not required, but sedation is generally recommended.[19]

### Devices and mechanisms

The focusing effect of the transducer allows high sound pressures to be delivered to a focal point without causing unwanted damage to other tissue. This increase in pressure can cause a number of effects including heating and cavitation.

The transducers differ from ultrasonic imaging probes that lots of people are familiar with. In this picture, two examples of HIFU transducers are shown on the left. They both have acoustic bowl-shaped lenses focus the sound inside the body. For comparison, on the right is an ultrasound imaging probe that might be used for cardiac imaging.
• Ultrasound sources may be used to generate regional heating and mechanical changes in biological tissue, e.g. in and cancer treatment.
• Focused ultrasound may be used to generate highly localized heating to treat cysts and tumors (benign or malignant), This is known as Magnetic Resonance guided Focused Ultrasound (MRgFUS) or High Intensity Focused Ultrasound (HIFU). These procedures generally use lower frequencies than medical diagnostic ultrasound (from 0.250 to 2 MHz), but significantly higher energies. HIFU treatment is often guided by MRI.
• Focused ultrasound may be used to break up kidney stones by lithotripsy.
• Ultrasound may be used for cataract treatment by phacoemulsification.
• Low-intensity ultrasound has been found to have physiological effects such as ability to stimulate bone-growth, and potential to temporarily disrupt the blood–brain barrier for drug delivery.[20][needs update]

In 2015 the FDA authorized two HIFU devices for the ablation of prostate tissue.[21]

## Mechanism of action

As an acoustic wave propagates through the tissue, part of it is absorbed and converted to heat. With focused beams, a very small region of heating can be achieved deep in tissues (usually on the order of millimeters). Tissue damage occurs as a function of both the temperature to which the tissue is heated and how long the tissue is exposed to this heat level in a metric referred to as "thermal dose". By focusing at more than one place or by scanning the focus, a volume can be thermally ablated.[22][23][24]

There is some evidence that HIFU can be applied to cancers to disrupt the tumor microenvironment and trigger an immune response, as well as possibly enhance the efficacy of immunotherapy.[25][26]

At high enough acoustic intensities, cavitation (microbubbles forming and interacting with the ultrasound field) can occur. Microbubbles produced in the field oscillate and grow (due to factors including rectified diffusion), and can eventually implode (inertial or transient cavitation). During inertial cavitation, very high temperatures occur inside the bubbles, and the collapse is associated with a shock wave and jets that can mechanically damage tissue.[27] Because the onset of cavitation and the resulting tissue damage can be unpredictable, it has generally been avoided in clinical applications thus far. However, researchers have been working on a method of controlling this cavitation, called histotripsy which often involves adding an agent that lowers the temperature at which cavitation occurs.[28][29][30]

### Theory

There are several ways to focus ultrasound—via a lens (for example, a polystyrene lens), a curved transducer, a phased array, or any combination of the three. This concentrates it into a small focal zone; it is similar in concept to focusing light through a magnifying glass. This can be determined using an exponential model of ultrasound attenuation. The ultrasound intensity profile is bounded by an exponentially decreasing function where the decrease in ultrasound is a function of distance traveled through tissue:

${\displaystyle I=I_{o}{e}^{-2\alpha \mathrm {z} }}$

${\displaystyle I_{o}}$ is the initial intensity of the beam, ${\displaystyle \alpha }$ is the attenuation coefficient (in units of inverse length), and z is distance traveled through the attenuating medium (e.g. tissue).

In this model, ${\displaystyle {\frac {-\partial I}{\partial \mathrm {z} }}=2\alpha I=Q}$[31] is a measure of the power density of the heat absorbed from the ultrasound field. Sometimes, SAR is also used to express the amount of heat absorbed by a specific medium, and is obtained by dividing Q by the tissue density. This demonstrates that tissue heating is proportional to intensity, and that intensity is inversely proportional to the area over which an ultrasound beam is spread—therefore, focusing the beam into a sharp point (i.e. increasing the beam intensity) creates a rapid temperature rise at the focus.[citation needed]

The amount of damage caused in the tissue can be modeled using Cumulative Equivalent Minutes (CEM). Several formulations of the CEM equation have been suggested over the years, but the equation currently in use for most research done in HIFU therapy comes from a 1984 paper by Dewey and Sapareto:[32]

${\displaystyle {\mathit {CEM}}=\int _{t_{o}}^{t_{f}}R^{T_{\mathrm {reference} }-T}dt}$

with the integral being over the treatment time, R=0.5 for temperatures over 43 °C and 0.25 for temperatures between 43 °C and 37 °C, a reference temperature of 43 °C, and time in minutes. This formula is an empirical formula derived from experiments performed by Dewey and Sapareto by measuring the survival of cell cultures after exposure to heat.[citation needed]

### Focusing

The ultrasound beam can be focused in these ways:

• Geometrically, for example with a lens or with a spherically curved transducer.
• Electronically, by adjusting the relative phases of elements in an array of transducers (a "phased array"). By dynamically adjusting the electronic signals to the elements of a phased array, the beam can be steered to different locations, and aberrations in the ultrasound beam due to tissue structures can be corrected.[citation needed]

## Image-guidance

Because of the non-invasive nature of HIFU, it is not possible to know where the focal position of the transducer is inside the body. For safe and accurate targeting, HIFU therapy requires monitoring and so is usually performed in conjunction with other imaging techniques.

X-ray CT is often used prior to transcranial therapy to measure the skull thickness. MRI is often used for localization of target volume, characterization of diffusion, perfusion, flow, and temperature.

Regular diagnostic ultrasound is of limited use during regular ablation because the acoustic properties of lesioned and unlesioned tissue differ very little. It can be useful if cavitation damage has occurred however as the region will become hyperechoic.[33] A promising new technique is ultrasonic thermography.

## History

The first investigations of HIFU for non-invasive ablation were reported by Lynn et al. in the early 1940s. Extensive important early work was performed in the 1950s and 1960s by William Fry and Francis Fry at the University of Illinois and Carl Townsend, Howard White and George Gardner at the Interscience Research Institute of Champaign, Ill., culminating in clinical treatments of neurological disorders. In particular High Intensity ultrasound and ultrasound visualization was accomplished stereotaxically with a Cincinnati precision milling machine to perform accurate ablation of brain tumors. Until recently, clinical trials of HIFU for ablation were few (although significant work in hyperthermia was performed with ultrasonic heating), perhaps due to the complexity of the treatments and the difficulty of targeting the beam noninvasively. With recent advances in medical imaging and ultrasound technology, interest in HIFU ablation of tumors has increased.

The first commercial HIFU machine, called the Sonablate 200, was developed by the American company Focus Surgery, Inc. (Milipitas, CA) and launched in Europe in 1994 after receiving CE approval, bringing a first medical validation of the technology for benign prostatic hyperplasia (BPH). Comprehensive studies by practitioners at more than one site using the device demonstrated clinical efficacy for the destruction of prostatic tissue without loss of blood or long term side effects. Later studies on localized prostate cancer by Murat and colleagues at the Edouard Herriot Hospital in Lyon in 2006 showed that after treatment with the Ablatherm (EDAP TMS, Lyon, France), progression-free survival rates are very high for low- and intermediate- risk patients with recurrent prostate cancer (70% and 50% respectively)[34] HIFU treatment of prostate cancer is currently[when?] an approved therapy in Europe[clarification needed], Canada, South Korea, Australia, and elsewhere.[citation needed] As of 2012, clinical trials for the Sonablate 500 in the United States are ongoing for prostate cancer patients and those who have experienced radiation failure.[35]

Use of magnetic resonance-guided focused ultrasound was first cited and patented in 1992.[36][37] The technology was later transferred to InsighTec in Haifa Israel in 1998. The InsighTec ExAblate 2000 was the first MRgFUS system to obtain FDA market approval[7] in the United States.

## Approval

Currently, there are HIFU systems approved to treat uterine fibroids, pain from bone metastases and the prostate in Asia, Canada, Europe, Israel, Latin America and the United States. There is regulatory approval to treat a range of cancers, including breast, kidney, liver, the pancreas and soft tissue sarcoma in Europe and Asia. There is a brain system approved in Europe, Korea and Russia to treat essential tremor, Parkinsonian tremor and neuropathic pain. Non-image guided HIFU devices may be marketed for cosmetic purposes (typically for body fat reduction) in some jurisdictions.

## References

1. ^ Overview of focused ultrasound
2. ^ Robertson, VJ; Baker, KG (2001). "A review of therapeutic ultrasound: Effectiveness studies". Physical Therapy. 81 (7): 1339–50. PMID 11444997.
3. ^ Elias, W. Jeffrey; Huss, Diane; Voss, Tiffini; Loomba, Johanna; Khaled, Mohamad; Zadicario, Eyal; Frysinger, Robert C.; Sperling, Scott A.; Wylie, Scott; Monteith, Stephen J.; Druzgal, Jason; Shah, Binit B.; Harrison, Madaline; Wintermark, Max (2013). "A Pilot Study of Focused Ultrasound Thalamotomy for Essential Tremor". New England Journal of Medicine. 369 (7): 640–8. doi:10.1056/NEJMoa1300962. PMID 23944301.
4. ^ Jeanmonod, Daniel; Werner, Beat; Morel, Anne; Michels, Lars; Zadicario, Eyal; Schiff, Gilat; Martin, Ernst (2012). "Transcranial magnetic resonance imaging–guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain". Neurosurgical Focus. 32 (1): E1. doi:10.3171/2011.10.FOCUS11248. PMID 22208894.
5. ^ Magara, Anouk; Bühler, Robert; Moser, David; Kowalski, Milek; Pourtehrani, Payam; Jeanmonod, Daniel (2014). "First experience with MR-guided focused ultrasound in the treatment of Parkinson's disease". Journal of Therapeutic Ultrasound. 2: 11. doi:10.1186/2050-5736-2-11. PMC . PMID 25512869.
6. ^ FDA News Release. "FDA approves first MRI-guided focused ultrasound device to treat essential tremor", FDA, July 11, 2016
7. ^ a b Food and Drug Administration Approval, ExAblate® 2000 System - P040003
8. ^ Fennessy, Fiona; Fischer, Krisztina; McDannold, Nathan; Jolesz, Ferenc; Tempany, Clare (2015). "Potential of minimally invasive procedures in the treatment of uterine fibroids: a focus on magnetic resonance-guided focused ultrasound therapy". International Journal of Women's Health. 7: 901–12. doi:10.2147/IJWH.S55564. PMC . PMID 26622192.
9. ^ Stewart, Elizabeth A.; Gostout, Bobbie; Rabinovici, Jaron; Kim, Hyun S.; Regan, Lesley; Tempany, Clare M. C. (2007). "Sustained Relief of Leiomyoma Symptoms by Using Focused Ultrasound Surgery". Obstetrics & Gynecology. 110 (2, Part 1): 279–87. doi:10.1097/01.AOG.0000275283.39475.f6. PMID 17666601.
10. ^ Jácome-Pita, F; Sánchez-Salas, R; Barret, E; Amaruch, N; Gonzalez-Enguita, C; Cathelineau, X (2014). "Focal therapy in prostate cancer: the current situation". Ecancermedicalscience. 8: 435. doi:10.3332/ecancer.2014.435. PMC . PMID 24944577.
11. ^ 'Cautious Optimism' for HIFU in Prostate Cancer. May 2016
12. ^ Aubry, Jean-Francois; Pauly, Kim; Moonen, Chrit; ter Haar, Gail; Ries, Mario; Salomir, Rares; Sokka, Sham; Sekins, Kevin; Shapira, Yerucham; Ye, Fangwei; Huff-Simonin, Heather; Eames, Matt; Hananel, Arik; Kassel, Neal; Napoli, Alessandro; Hwang, Joo; Wu, Feng; Zhang, Lian; Melzer, Andreas; Kim, Young-sun; Gedroyc, Wladyslaw (2013). "The road to clinical use of high-intensity focused ultrasound for liver cancer: technical and clinical consensus". Journal of Therapeutic Ultrasound. 1 (1): 1–13. doi:10.1186/2050-5736-1-13. PMC . PMID 25512859.
13. ^ Therapeutic Ultrasound. New York: Springer. 2016. ISBN 978-3-319-22536-4.
14. ^ "Philips Sonalleve receives CE Mark for MR-guided focused ultrasound ablation of metastatic bone cancer" (Press release). Philips Healthcare. April 20, 2011. Archived from the original on October 5, 2013. Retrieved October 4, 2013.
15. ^ Wu, F.; Wang, Z.-B.; Zhu, H.; Chen, W.-Z.; Zou, J.-Z.; Bai, J.; Li, K.-Q.; Jin, C.-B.; Xie, F.-L.; Su, H.-B. (2005). "Feasibility of US-guided High-Intensity Focused Ultrasound Treatment in Patients with Advanced Pancreatic Cancer: Initial Experience". Radiology. 236 (3): 1034–40. doi:10.1148/radiol.2362041105. PMID 16055692.
16. ^ Application and FDA permission to market a device, 18 August 2011
17. ^ "510(k) Premarket Notification - K112626". 510(k) Premarket Notification Database. Food and Drug Administration. Retrieved March 8, 2015. Premarket notification, device in classification "focused ultrasound for tissue heat or mechanical cellular disruption", classification description "Focused ultrasound stimulator system for aesthetic use"
18. ^ http://digital.eyeworld.org/i/325050-jun-2014/57
19. ^ Therapeutic Ultrasound. New York: Springer. 2016. pp. 3–20. ISBN 978-3-319-22536-4.
20. ^ Hynynen, Kullervo; McDannold, Nathan; Sheikov, Nickolai A.; Jolesz, Ferenc A.; Vykhodtseva, Natalia (2005). "Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications". NeuroImage. 24 (1): 12–20. doi:10.1016/j.neuroimage.2004.06.046. PMID 15588592.
21. ^
22. ^ Huisman, Merel; Lam, Mie K; Bartels, Lambertus W; Nijenhuis, Robbert J; Moonen, Chrit T; Knuttel, Floor M; Verkooijen, Helena M; van Vulpen, Marco; van den Bosch, Maurice A (2014). "Feasibility of volumetric MRI-guided high intensity focused ultrasound (MR-HIFU) for painful bone metastases". Journal of Therapeutic Ultrasound. 2: 16. doi:10.1186/2050-5736-2-16. PMC . PMID 25309743.
23. ^ Köhler, Max O.; Mougenot, Charles; Quesson, Bruno; Enholm, Julia; Le Bail, Brigitte; Laurent, Christophe; Moonen, Chrit T. W.; Ehnholm, Gösta J. (2009). "Volumetric HIFU ablation under 3D guidance of rapid MRI thermometry". Medical Physics. 36 (8): 3521–35. Bibcode:2009MedPh..36.3521K. doi:10.1118/1.3152112. PMID 19746786.
24. ^ Monteith, Stephen J.; Kassell, Neal F.; Goren, Oded; Harnof, Sagi (2013). "Transcranial MR-guided focused ultrasound sonothrombolysis in the treatment of intracerebral hemorrhage". Neurosurgical Focus. 34 (5): E14. doi:10.3171/2013.2.FOCUS1313. PMID 23634918.
25. ^ Haen, Sebastian P.; Pereira, Philippe L.; Salih, Helmut R.; Rammensee, Hans-Georg; Gouttefangeas, Cécile (2011). "More Than Just Tumor Destruction: Immunomodulation by Thermal Ablation of Cancer". Clinical and Developmental Immunology. 2011: 1–19. doi:10.1155/2011/160250. PMC . PMID 22242035.
26. ^ Wu, Feng (2013). "High intensity focused ultrasound ablation and antitumor immune response". The Journal of the Acoustical Society of America. 134 (2): 1695–701. Bibcode:2013ASAJ..134.1695W. doi:10.1121/1.4812893. PMID 23927210.
27. ^ Leighton, T.G. (1997). Ultrasound in food processing. Chapter 9: The principles of cavitation: Thomson Science, London, Blackie Academic and Professional. pp. 151–182.
28. ^ Maxwell, Adam; Sapozhnikov, Oleg; Bailey, Michael; Crum, Lawrence; Xu, Zhen; Fowlkes, Brian; Cain, Charles; Khokhlova, Vera (2012). "Disintegration of Tissue Using High Intensity Focused Ultrasound: Two Approaches That Utilize Shock Waves" (PDF). Acoustics Today. 8 (4): 24. doi:10.1121/1.4788649.
29. ^ G., Leighton, T. (1994). The acoustic bubble. London: Academic Press. ISBN 9780124419209. OCLC 30091395.
30. ^ Wrenn, Steven P.; Dicker, Stephen M.; Small, Eleanor F.; Dan, Nily R.; Mleczko, Michał; Schmitz, Georg; Lewin, Peter A. (2012). "Bursting Bubbles and Bilayers". Theranostics. 2 (12): 1140–59. doi:10.7150/thno.4305. PMC . PMID 23382772.
31. ^ P Hariharan et al. (2007)[full citation needed]
32. ^ Sapareto, Stephen A.; Dewey, William C. (1984). "Thermal dose determination in cancer therapy". International Journal of Radiation Oncology, Biology, Physics. 10 (6): 787–800. doi:10.1016/0360-3016(84)90379-1. PMID 6547421.
33. ^ Chan, Arthur H.; Vaezy, Shahram; Crum, Lawrence A. (2003). "High-intensity Focused Ultrasound". AccessScience. McGraw-Hill Education. doi:10.1036/1097-8542.YB031005.
34. ^ Gelet, A; Murat, François-Joseph; Poissonier, L (2007). "Recurrent Prostate Cancer After Radiotherapy – Salvage Treatment by High-intensity Focused Ultrasound". European Oncological Disease. 1 (1): 60–2.
35. ^ USHIFU (2012). "Clinical Information about HIFU in the U.S". Archived from the original on August 7, 2009.
36. ^ Hynynen, K.; Damianou, C.; Darkazanli, A.; Unger, E.; Levy, M.; Schenck, J. F. (1992). "On-line MRI monitored noninvasive ultrasound surgery". Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society: 350–351. doi:10.1109/IEMBS.1992.5760999. ISBN 978-0-7803-0785-8.
37. ^ US 5247935, "Magnetic resonance guided focussed ultrasound surgery", issued March 19, 1992